Mechanism That Helps in Coping With Stress also Boosts Cancer

A new research has revealed that heat-shock factor 1 (HSF1) that helps in coping with environmental stresses, including heat and toxic exposures, also gives cancerous tumors a boost.

This finding has researchers excited as targeting this mechanism could help treat cancer, and may also have implications for the treatment of neurodegenerative and other diseases.

The researchers found that loss of the master controller of the "heat-shock response" significantly restricted the spontaneous development of tumors in mice genetically predisposed to developing cancer, and those exposed to cancer-causing chemicals.

The researchers also reported the reduction of the so-called heat-shock factor 1 (HSF1) in diverse previously established human cancer cell lines strongly damaged their growth and survival, while having little effect on normal cells.

"At a fundamental level, the ability of HSF1 to enable lethal malignancies is an unfortunate legacy of its ancient role in enhancing the survival of normal cells exposed to diverse acute and chronic stresses," said Susan Lindquist, a Howard Hughes investigator at the Whitehead Institute for Biomedical Research.

"We expected it would have some effect on cancer, but we were surprised at the degree."

Researchers said that the heat-shock response is one of the most ancient and evolutionarily conserved protective mechanisms found in nature.

While environmental insults provoke a variety of adaptive physiological responses to help organisms cope with specific stressors, the dramatic induction of heat-shock proteins (HSPs) is an essential unifying component of most of them.

The HSPs, which are under the control of a small family of heat-shock factors (HSFs), guard against the abnormal activity of other proteins in the face of stressors such as heat and oxygen starvation.

Though scientists had long noted that HSP levels increase in many cancer cells, whether the stress management proteins played a causal, supportive, or inhibitory role in cancer remained an unanswered question.

"On the one hand, given its prominent role in helping cells cope with stressful insults, HSF1 might promote [cancer's formation] by facilitating cellular adaptation to the malignant lifestyle. On the other hand, given its general role in enhancing longevity, HSF1 might assist organisms in combating malignancy," she said.

In order to find out, the researchers first looked to a common mouse model of skin cancer, in which the animals' are exposed to cancer-causing chemicals. Mice unable to switch on the heat-shock response were "far more resistant" to tumor formation than normal mice were under those conditions, they found. It took the mutant mice five weeks longer to develop tumors. They were less likely to develop cancer and, when they did, had fewer and smaller tumors. The HSF1-deficient mice also lived longer.

After that, researchers examined mice predisposed to develop cancer due to a deficiency of the tumor suppressor p53, the most frequently mutated gene in human cancers. Again, they found, the HSF1-deficient animals lived tumor-free for dramatically longer. Indeed, even cancer-prone animals lacking just one working copy of HSF1 lived longer than normal animals did. Through studies in cultured mouse cells, they found further evidence that HSF1 supports the transformation to cancer by orchestrating a variety of basic cell functions, including proliferation, survival, protein synthesis, and glucose metabolism.

Following that, they examined the role of HSF1 in normal and cancerous human cells, including those derived from the breast, prostate, and cervix. In every case, they found that the cancerous cells, but not the normal cells, were strongly affected by HSF1's inhibition. Those findings led them to conclude that "HSF1 function helps to maintain the growth and survival of human cancer cells with diverse underlying malignant defects."

The new findings are reported in the Sept. 21, 2007, issue of Cell, a publication of Cell Press.

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